Common variable immunodeficiency (CVID) in horses is a natural primary immunologic condition characterized by late-onset B cell lymphopenia or depletion, hypo- or agammaglobulinemia, and recurrent bacterial infections. Although these equine patients do not respond to tetanus-toxoid vaccination with specific-immunoglobulin production, they do respond to the pneumococcal polysaccharide (PPS) antigen. In the absence of conventional B cells, we suspect that the CVID horse distinct response to PPS involves the presence and function of B1 cells, which are spared in these patients. This proposal explores a better understanding of B1 cell response and its role in protection against infection in patients with defective conventional B2 cell function. B1 cells differ from B2 cells in their distribution and innate immune response characteristics, including the potential to respond to antigens in a T cell-independent manner. In addition to directly neutralizing pathogens at the level of the mucosa, B1 cell antibodies also prevent viral and bacterial spread to vital organs through the blood stream. We would like to explore the function of B1 cells because they survive in many forms of humoral immunodeficiencies;the production of antigen-specific antibodies can be stimulated in mouse models with primary B1 cell function;and B1 cells are the largest population of immune cells in human fetal spleen and umbilical cord. We identified a natural humoral immunodeficiency in the horse that provides a rare opportunity to study distinctly the role of B1 cells in a setting that is uncomplicated by the presence of conventional B2 cells. In addition, we will develop a horse-mouse chimera (SCID-Eq) to complement the studies in the immunodeficient horses. New strategies that explore the patients own immune system defense should improve clinical outcome of CVID. PUBLIC HEALTH RELEVANCE: Common variable immunodeficiency (CVID) in horses is a natural primary immunologic condition characterized by late-onset B cell lymphopenia or depletion, hypo- or agammaglobulinemia, and recurrent bacterial infections. We propose the CVID horse as a model of study for CVID in humans because they share many similarities in clinical disease and patient care. We also propose to develop a horse-mouse chimera (SCID-Eq) to complement studies in the immunodeficient horse. Our objective is to investigate new strategies that explore the patients'own immune defense to improve clinical outcome.